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Isaac Ginsburg,1 Maya Korem,2 Erez Koren,3 James Varani4 1Institute of Dental Sciences, Faculty of Dental Medicine, The Hebrew University, Jerusalem, Israel; 2Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 3Research and Development Department, Clexio Biosciences Ltd, Petah Tikva, Israel; 4Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, USA Abstract: We postulate that the extensive cell and tissue damage inflicted by many infectious, inflammatory and post-inflammatory episodes is an enled result of a synergism among the invading microbial agents, host neutrophils and dead and dying cells in the nidus. Microbial toxins and other metabolites along with the plethora of pro-inflammatory agents released from activated neutrophils massively recruited to the infectious sites and high levels of cationic histones, other cationic peptides, proteinases and Th1 cytokines released from activated polymorphonuclear neutrophils (PMNs) and from necrotized tissues may act in concert (synergism) to bring about cell killing and tissue destruction. Multiple, diverse interactions among the many potential pro-inflammatory moieties have been described in these complex lesions. Such infections are often seen in the skin and aerodigestive tract where the tissue is exposed to the environment, but can occur in any tissue. Commonly, the tissue-destructive infections are caused by group A streptococci, pneumococci, Staphylococcus aureus, meningococci, Escherichia coli and Shigella, although many other microbial species are seen on occasion. All these microbial agents are characterized by their ability to recruit large numbers of PMNs. Given the complex nature of the disease process, it is proposed that, to treat these multifactorial disorders, a “cocktail” of anti-inflammatory agents combined with non-bacteriolytic antibiotics and measures to counteract the critical toxic role of cationic moieties might prove more effective than a strategy based on attacking the bacteria alone. Keywords: synergism, tissue damage, bacterial toxin, bacteriolysis, cationic proteins, sepsis

Isaac Ginsburg,1 Peter Vernon van Heerden,2 Erez Koren1 1Institute of Dental Sciences, Faculty of Dental Medicine, The Hebrew University of Jerusalem, 2General Intensive Care Unit, Hadassah University Hospital, Jerusalem, Israel Abstract: This paper describes the evolution of our understanding of the biological role played by synthetic and natural antimicrobial cationic peptides and by the highly basic nuclear histones as modulators of infection, postinfectious sequelae, trauma, and coagulation phenomena. The authors discuss the effects of the synthetic polymers of basic poly α amino acids, poly l-lysine, and poly l-arginine on blood coagulation, fibrinolysis, bacterial killing, and blood vessels; the properties of natural and synthetic antimicrobial cationic peptides as potential replacements or adjuncts to antibiotics; polycations as opsonizing agents promoting endocytosis/phagocytosis; polycations and muramidases as activators of autolytic wall enzymes in bacteria, causing bacteriolysis and tissue damage; and polycations and nuclear histones as potential virulence factors and as markers of sepsis, septic shock, disseminated intravasclar coagulopathy, acute lung injury, pancreatitis, trauma, and other additional clinical disorders Keywords: histones, sepsis, septic shock

Septic peritonitis (SP) is a life-threating condition. Determining prognosis for dogs suffering from SP remains challenging. Extracellular histones exert cytotoxic, prothrombotic and proinflammatory effects. Our objective was to investigate serum general histone concentrations (sHs) as biomarkers of disease severity and outcome in dogs with naturally occurring SP. Blood samples were collected upon admission and 24 hours post admission from 21 dogs with SP and from 7 healthy controls. Serum general histone concentrations (median; IQR) upon admission were higher in dogs with SP compared to controls (34.2 ng/ml; 39.1 ng/ml vs. 7.3 ng/ml; 1.7 ng/ml; P=0.001) and sHs significantly decreased 24 hours post admission in dogs with SP (34.4 ng/ml; 39.3 ng/ml vs. 24.2 ng/ml; 11 ng/ml; P=0.018). Serum histones were higher among survivors compared to non-survivors (45.5 ng/ml; 37 ng/ml vs. 24.0 ng/ml; 12 ng/ml; P=0.03). This data demonstrates that sHs concentrations significantly increase in dogs with SP and decrease after hospitalization. Future studies are warranted to investigate the reverse relationship between outcome and sHs. [ABSTRACT FROM AUTHOR]